Project Summary Bromodomain proteins function as epigenetic ?readers? and play a key role in epigenetic regulation of gene transcription by binding to acetylated lysine residues (Ac-K) on histone tails. BET proteins have two conserved N-terminal bromodomains (BD1 and BD2). The bromodomain and extra-terminal domain (BET) inhibitors have been extensive studied for tumors treatment in the past few years. Recently, BET inhibitors have been reported to play a key role in brain functions, such as learning and memory, also show a therapeutic potential for substance abuse. BET proteins have diverse roles in regulating tissue-specific transcriptional programs, therefore, targeting of specific BET domains will be important for investigating the safety of potential therapeutics. Unfortunately, there are no suitable non-invasive imaging tools for investigating BET expression and activity in animals or in man. The development of techniques for visualizing specific BET domains in vivo represents a key step in understanding both the normal function and pathophysiology of BET in brain. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with the specific BET domains. The project is designed to develop novel PET imaging probes for BD2 domain of BET. We will modify the structure of our lead compounds and label BET inhibitors with fluorine-18 and evaluate the potential of these molecules to serve as F-18 radiotracers for BET in humans by imaging their distribution and pharmacokinetics in rodents and non-human primates.